Alzheimer and cardiovascular genetic scores and cognition: the FINGER randomized controlled trial

Alzheimer's disease and coronary artery disease are common late-life chronic conditions and share multiple risk factors, including the apolipoprotein E (APOE) ε4 allele. A meta-analysis of two multidomain lifestyle intervention trials found greater cognitive benefits in APOE4 carriers compared with non-carriers. This study investigated the impact of genetic risk scores for Alzheimer's disease and coronary artery disease (AD-GRS, CAD-GRS) on cognition in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) randomized controlled trial. FINGER included 1259 at-risk individuals without dementia from the general population, aged 60-77 years. Participants were randomized 1:1 to a 2-year multidomain lifestyle intervention or regular health advice. The primary outcome was change in cognition based on a modified Neuropsychological Test Battery (14 tests). Previous comprehensive AD-GRS and CAD-GRS were calculated using genome-wide association study data (1177 participants, with 585 in the control and 592 in the intervention groups, exploratory analysis). The intervention-control difference in annual overall cognition change (95% confidence interval) for participants with AD-GRS above/below the median (i.e. higher/lower risk) was 0.032 (0.002-0.063) versus 0.017 (-0.011 to 0.045), and for CAD-GRS above/below the median was 0.031 (0.002 to 0.059) versus 0.016 (-0.012 to 0.044). AD-GRS or CAD-GRS were not significantly related to the intervention effect overall (P > 0.46), but for AD-GRS there were differences between females and males (P = 0.024). The intervention-control difference in annual overall score change was 0.045 (0.004 to 0.087) for higher-risk females, 0.003 (-0.040 to 0.047) for lower-risk females, 0.019 (-0.026 to 0.064) for higher-risk males, and 0.027 (-0.009 to 0.064) for lower-risk males. People with genetic susceptibility for Alzheimer's disease/dementia or coronary artery disease can benefit from multidomain lifestyle interventions. Although the findings for the AD-GRS and CAD-GRS risk groups were similar to APOE4 carrier status, with additional gender differences for AD-GRS, these exploratory findings need to be verified across several multidomain lifestyle trials to ensure adequate statistical power and inclusion of genetically diverse populations.